ABSTRACT. Liver tumors represent the third leading cause of cancer-related mortality in the world. Surgery (resection or transplant) have formed the historical basis for treating hepatic tumors with intent to cure. However, advanced disease staging at diagnosis (including intra- and extra-hepatic metastatic disease), a paucity of transplantable organs, underlying hepatic pathology, intrahepatic tumor location, and extensive vascular involvement often contrive to limit surgical intervention as viable options. Thermal ablation has emerged as an alternative to resection. While potentially curative, tumor vascularization and location (relative to vital structures) often restricts thermal ablation to a subset of patients with liver tumors. As a result, less than 25% of all patients diagnosed with hepatic tumors are amenable to existing treatment with intent to cure, and five-year survival rates (15-25%) have remained largely unchanged over the last three decades. Innovative approaches are required to develop new treatment options for those diagnosed with liver tumors. Irreversible electroporation (IRE) is an alternative to thermal ablation, whereby rapid electrical pulses are delivered between electrodes placed in or around the tumor. The electric field generated during IRE delivery leads to formation of permanent cell membrane defects that render cells incapable of regulating normal homeostasis and induces cell death. Because IRE induces minimal thermal necrosis or tissue devitalization, IRE offers the advantage of sparing the structural integrity of the underlying tissue architecture. However, clinical and technical complexities associated with existing IRE means it has been slow to be adopted clinically. We have developed a novel high-frequency IRE (HFIRE) system that overcomes many of the technical challenges associated with IRE by delivering ultrashort, bipolar electrical pulses. However, the HFIRE system does not overcome the clinical challenge of requiring multiple electrodes to be placed in a challenging anatomic environment or the inability to accurately monitor ablation progress in real-time. This led us to hypothesize that creating a single needle-dual electrode HFIRE (SN-HFIRE) delivery platform will directly enable development of this technology to selectively treat hepatic tumors not amenable to resection or thermal ablation. To test this hypothesis three Aims are proposed. Aim 1 Will employ a novel ex vivo machine perfused liver model to test the functionality of existing SN-HFIRE devices, and to develop and evaluate novel SN-HFIRE devices incorporating thermally-mitigating materials for HFIRE delivery. These studies will be performed in conjunction with real-time measurement of tissue-ablation properties; Aim 2 Will define the clinical potential of SN- HFIRE in the complex in vivo environment using acute and chronic large animal (swine) liver models; Aim 3 will establish the clinical viability of SN-HFIRE by treating canine HCC patients using a treat-and-resect protocol. The proposed approaches will build on the technical and clinical expertise of the research groups assembled to develop an innovative, translational approach to treating and managing those diagnosed with untreatable hepatic tumors, while simultaneously creating a novel ablation technology that is readily adaptable for treating other, inoperable solid tumors.